a Guideline for the Clinical Management of Opioid Addiction

a Guideline for the Clinical Management of Opioid Addiction Published 2015

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Vancouver Coastal Health & Providence Health Care Opioid Use Disorder Treatment Guideline Committee Dr. Keith Ahamad, MD Addiction Medicine Consult Team, St. Paul s Hospital, Providence Health Care; Addiction Medicine Physician, Vancouver Detox Dr. Cassandra Djurfors, MD Medical Coordinator, Pender Community Health Centre, Vancouver Coastal Health Dr. Ronald Joe, MD Associate Medical Director, Addiction Services, Vancouver Coastal Health Dr. Venu Karapareddy, MD Addiction Psychiatrist, Vancouver Coastal Health Ms. Mary Marlow, RPN Mental Health and Substance Use Services, Vancouver Coastal Health Dr. Garth McIver, MD Addiction Physician (retired) and Medical Director (retired), VCH Addiction Services Dr. Mark McLean, MD Physician Lead, Addiction Medicine Consult Team, St. Paul s Hospital, Providence Health Care; Addiction Medicine Physician, Vancouver Detox Dr. Daniel Paré, MD Medical Coordinator, Downtown Community Health Centre Primary Care and Addiction Physician, Assertive Community Treatment (ACT) Team, Vancouver Coastal Health Dr. Christy Sutherland, MD Medical Director, Portland Hotel Society Dr. Kenneth Tupper, PhD British Columbia Ministry of Health Dr. Evan Wood, MD, PhD (Committee Chair) Medical Director, Community Addiction Services, Vancouver Coastal Health/Providence Health Care; Co-director, Urban Health Research Initiative, BC Centre for Excellence in HIV/AIDS; Professor of Medicine, UBC Conflicts of interest None of the committee members had conflicts of interest to declare.

Acknowledgements Dr. Rolando Barrios, Senior Medical Director, Vancouver Coastal Health Ms. Laura Case, Chief Operating Officer, Vancouver Coastal Health Ms. Anne McNabb, Director Mental Health and Addiction Urban Site Lead, Vancouver Coastal Health Mr. Andrew MacFarlane, Director Mental Health and Addiction Inner City and Regional Program Director Mental Health and Addiction Program The B.C. Centre for Excellence in HIV/AIDS The authors thank Ms. Pauline Voon (PhD Candidate) for primary research and writing assistance in preparing this document, as well as Ms. Deborah Graham and Ms. Emily Wagner for their editorial and administrative assistance, and Ms. Lianlian Ti and Mr. James Nakagawa for their assistance with document layout and design. Peer Reviewers Dr. Rashmi Chadha, MBChB, MScCH, CCFP, MRCGP: Addiction and Family Medicine, Physician, Vancouver Coastal Health Dr. Ramm Hering, MD, CCFP, MSc, Dip PH: Addiction and Family Medicine Physician, Pandora Clinic, Victoria, BC Dr. P. Todd Korthuis, MD, MPH: Associate Professor of Medicine and Public Health Preventive Medicine, Oregon Health and Science University Dr. Scott MacDonald, MD: Physician Lead, Providence Crosstown Clinic Dr. David C. Marsh, MD, CCSAM: Deputy Dean, Professor and Associate Dean Community Engagement, Northern Ontario School of Medicine Dr. Christian G. Schütz MD, PhD, MPH, FRCPC: Research and Education Clinical Manager, Burnaby Centre for Mental Health and Addictions Ms. Kathleen Perkin: Manager, Harm Reduction Policy, British Columbia Ministry of Health From Grief to Action Board Members BC Association of People on Methadone (BCAPOM) Board Members, shared for feedback on August 20, 2015 Ms. Mae Burrows, Family Advocate

Table of contents Executive summary...1 Summary of recommendations... 3 Introduction...4 Guideline development...4 Possible treatment options...5 Literature review...5 I Withdrawal management strategies...6 II Agonist treatments...9 III Alternative agents... 13 IV Combination approaches and movement between approaches...14 V Psychosocial supports...16 Expert guideline... 17 Appendices Appendix 1: Induction and dosing guidelines for buprenorphine/naloxone...20 Appendix 2: Dosing recommendations for slow-release oral morphine (SROM)...23 Appendix 3: Take-home dosing recommendations for oral agonist therapy...25 References... 27 While the Vancouver Coastal Health Authority ( VCH ) and Providence Health Care ( PHC ) have made every effort to ensure the accuracy of the information contained in this treatment guideline, please note that the information is provided as is and that VCH and PHC make no representation or warranty of any kind, either expressed or implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest extent possible under applicable law, VCH disclaims and will not be bound by any express, implied or statutory representation or warranty (including without limitation representations or warranties of title or non-infringement).

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Executive summary Opioid use disorder is one of the most challenging forms of addiction facing the health care system in British Columbia. Despite an excellent guideline by the College of Physicians and Surgeons of British Columbia regarding the safe use of methadone maintenance treatment (MMT), there remains a need for an evidence-based guideline articulating the full range of therapeutic options for the optimal treatment of adults and young adults with varying presentations of opioid use disorder. This lack of a comprehensive guideline has been a challenge for Vancouver Coastal Health (VCH) and the provincial health system, and has resulted in a lack of awareness and use of the full armamentarium of medical and psychosocial treatments available for managing opioid dependence among health care providers in substance use services and the addiction care continuum. To address this, an interdisciplinary committee comprising individuals from VCH, Providence Health Care and the Ministry of Health developed the following expert guidelines. These guidelines were subsequently peer-reviewed by patient groups, local and international experts in the field. The recommendations in these guidelines are based on a systematic review and use of a traditional hierarchy of evidence whereby meta-analysis of randomized clinical trials was given the most weight, followed by individual clinical trials, observational reports and expert opinion. While this guideline supports the diversity of possible treatments available for individuals presenting with opioid use disorder, it strongly recommends against a strategy involving only withdrawal management (often referred to as detox ), since this approach has been associated with elevated rates of infections such as HIV and hepatitis C, elevated rates of overdose deaths in comparison to providing no treatment, and nearly universal relapse when implemented without plans for transition to long-term evidence-based treatment. However, this guideline acknowledges the 1

importance of strengthening the residential treatment system with a view to aiding individuals seeking long-term cessation of opioid use who do not wish to initially pursue pharmacological treatment for opioid dependence, but may still wish to use other various pharmacotherapies for symptom management during withdrawal. In addition, this guideline strongly endorses the use of buprenorphine/naloxone as a preferred first-line treatment when opioid substitution pharmacotherapy is being considered for the treatment of opioid use disorder and contraindications have been ruled out. This recommendation is in line with the growing body of research suggesting that buprenorphine has a six times greater safety profile than methadone in terms of overdose risk, in addition to other comparative advantages. Notably, methadone has recently been reported to be involved in approximately 25% of prescriptionopioid-related deaths in British Columbia. However, this guideline also endorses the use of methadone as a first-line therapy when pharmacotherapy is appropriate and contraindications to buprenorphine/naloxone exist, and supports the use of methadone as a second-line option when buprenorphine/naloxone treatment proves to have limitations or is initially ineffective. Beyond these three possible first-line or second-line treatment approaches, this guideline also reviews the international evidence regarding the use of alternative pharmacotherapies for the treatment of opioid use disorder, including long-acting oral morphine as well as injectable opioid medications that must be provided via witnessed injection in a structured and supervised setting. Finally, this guideline recognizes that most individuals will benefit from the ability to move between treatments, depending on the individual s initial presentation, comorbidities, treatment preferences and response to treatment. This includes intensification (e.g., initiating a pharmacotherapy when a non-pharmacotherapy-based strategy is unsuccessful) as well as routine strategies to de-intensify treatment (e.g., transition from methadone to buprenorphine/ naloxone) when patients are effectively treated and wish to transition to treatments that allow for more flexible take-home dosing (e.g., buprenorphine/naloxone). With the greater incorporation of evidence-based medicine principles into the treatment of opioid use disorder through adherence to data-driven therapeutic guidelines, there is substantial potential to improve systems of treatment for opioid use disorder and significantly reduce the burden of disease and health and social service costs associated with untreated opioid addiction. In order to address these costs, while recognizing the finite funding available for health services, prioritization and proportionate funding should be reasonably allocated toward the recommendations laid out in this guideline. 2

Summary of recommendations Recommendation Approaches to avoid Withdrawal management alone (i.e., detox without transition to longer term treatment) is not recommended, since this approach has been associated with elevated rates of HIV infection and overdose death. Possible first-line treatment options Initiate opioid agonist treatment with buprenorphine/ naloxone whenever feasible to reduce toxicities and facilitate safer take home dosing. Initiate opioid agonist treatment with methadone when treatment with buprenorphine/naloxone is not preferable (e.g., challenging induction, high risk for drop-out). When opioid withdrawal is being medically supervised, this can generally be safely done on an outpatient rather than inpatient basis but should include ongoing addiction treatment. Adjunct or alternative treatment options For individuals responding poorly to buprenorphine/ naloxone, transition to methadone. For individuals with successful and sustained response to methadone desiring treatment simplification, consider transition to buprenorphine/naloxone. For individuals with successful and sustained response to agonist treatment desiring medication cessation, consider slow taper over 12 months. Psychosocial supports may be routinely offered in conjunction with pharmacological treatment. For patients wishing to avoid initial treatment with an opioid agonist therapy, provide outpatient opioid agonist taper (preferably methadone or buprenorphine/naloxone), with subsequent immediate referral to intensive outpatient or residential addiction treatment. Oral naltrexone can be considered as an adjunct in this context. Quality of evidence* Moderate High High Moderate High Moderate Moderate Moderate Low For more Strength of information recommendation* see page Strong 6 Strong 10 Strong 9 Strong 6 7 Strong 14 Strong 14 Strong 6 Conditional 16 Weak 6, 14 * GRADE criteria were used to ascertain and describe the quality of evidence (possible categories include: high, moderate, low, very low) and strength of recommendation (possible categories include: strong, conditional, weak). 1 3

Introduction While Canadian estimates are lacking, opioid use disorder is estimated to affect approximately 1.4% of Americans. 2 Opioid use disorder may involve the use of illicitly obtained opioids (e.g., heroin) or, increasingly, diverted or misused prescription opioid medications. As a result, opioid use disorder is often a chronic illness associated with elevated rates of morbidity and mortality. British Columbia has benefited from a well established methadone maintenance program stewarded by the College of Physicians and Surgeons of British Columbia. 3,4 The Methadone Maintenance Committee, which oversees the methadone maintenance program, has developed an expert guideline for the use of methadone maintenance treatment that is periodically updated and is an excellent resource for physicians wishing to prescribe methadone for opioid use disorder. 5 However, in recent years, a number of additional opioid agonist treatment options have emerged for the treatment of opioid addiction. Coinciding with this, evidence-based reviews have increasingly described the benefits, side-effect profiles and safety concerns surrounding the various approaches to the treatment of opioid use disorder. This literature, which is reviewed in detail below, enables the development of strategies for the treatment of opioid use disorder that employ different approaches based on individual patient circumstances and comorbidities and recognize that treatment can be intensified or simplified depending on short- and long-term response to treatment. To address the health care needs within the VCH catchment area, and to best address the needs of patients with opioid use disorder in an evidence-based, cost-effective way, an expert panel was convened by VCH to discuss this literature and propose a guideline for VCH with respect to the optimal treatment and care of individuals with opioid addiction. What follows is a description of the literature supporting these recommendations and ultimately a description of the treatment pathways being recommended by this panel for use by health care providers across VCH. These guidelines relate to the clinical management of established opioid addiction among adults and youth with opioid use disorder, 6 while treatment options for specialized populations affected by opioid use disorder (e.g., pregnant women) are beyond the scope of this guideline. Guideline development The recommendations in these guidelines are based on a systematic review and use of a traditional hierarchy of evidence whereby meta-analysis of randomized clinical trials was given the most weight, followed by individual clinical trials, observational reports and expert opinion. In addition, the literature reviewed in this guideline was summarized as per the criteria set out by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, 1 which is a system that has been applied to high-level guideline and systematic review development processes, including all policies and guidelines developed by the World Health Organization. 7 The GRADE system takes into consideration both the quality of evidence (high, moderate, low or very low, with quality determined by both study design and other important factors such as weighing risks versus benefits, likelihood of bias, or limited or inconsistent results) and the strength of recommendation (strong, conditional, or weak). All members of the VCH Opioid Use Disorder Treatment Guideline Committee reviewed and reached a majority agreement on the guidelines and recommendations after several rounds of revision. 4

Possible treatment approaches Possible treatment options considered included: withdrawal management from opioid drugs and an outpatient or residential treatment referral; opioid agonist therapy, particularly with methadone, buprenorphine/naloxone or other agonists; and opioid antagonist medications such as naltrexone. The guideline also considered the research regarding the integration of psychosocial treatments and supports for opioid use disorder. Although evidence presented here is generally extrapolated from studies conducted in adult populations, with this caveat, the consensus of the committee is that recommendations are relevant and applicable to adult and young adult populations. Literature review Table 1. Treatment options for opioid use disorder Withdrawal Management 1 3 Agonist Therapies Alternative Approaches Tapered methadone, buprenorphine, or alpha-2 adrenergic agonists + psychosocial treatment 4 + residential treatment + oral naltrexone 5 Buprenorphine/ naloxone 6 (preferred) Methadone 7,8 Slow-release oral morphine 9 Diacetylmorphine 10 LOW If opioid use continues, consider treatment intensification» TREATMENT INTENSITY HIGH Where possible, «simplify treatment Citations 1. Amato L, Davoli M, Minozzi S, Ferroni E, Ali R, Ferri M. Methadone at tapered doses for the management of opioid withdrawal. Cochrane Database Syst Rev 2013;2:CD003409. 2. Gowing L, Ali R, White JM. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev 2009:CD002025. 3. Gowing L, Farrell MF, Ali R, White JM. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev 2014;3:CD002024. 4. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev 2011:CD005031. 5. Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst Rev 2011:CD001333. 6. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2014;2:CD002207. 7. Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009:CD002209. 8. Faggiano F, Vigna-Taglianti F, Versino E, Lemma P. Methadone maintenance at different dosages for opioid dependence. Cochrane Database Syst Rev 2003:CD002208. 9. Ferri M, Minozzi S, Bo A, Amato L. Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane Database Syst Rev 2013;6:CD009879. 10. Ferri M, Davoli M, Perucci CA. Heroin maintenance for chronic heroin-dependent individuals. Cochrane Database Syst Rev 2011:CD003410. 5

I Withdrawal management * strategies ALPHA-2 ADRENERGIC AGONISTS Compared to placebo, alpha-2 adrenergic agonists (e.g., clonidine) have been found to be effective for opioid withdrawal management in terms of a lesser likelihood of severe withdrawal symptoms and higher probability of completing treatment. 8 Signs and symptoms of withdrawal appear to both occur and resolve earlier with alpha-2 adrenergic agonists. The chances of completing treatment of withdrawal are similar between alpha-2 adrenergic agonists and methadone, but alpha-2 adrenergic agonists tend to require shorter treatment durations. However, compared to methadone tapers, alpha-2 adrenergic The majority of patients still relapse to opioid use if a strategy involving only withdrawal management is employed. agonists are somewhat less effective in mitigating withdrawal symptoms, and are more likely to present adverse effects such as hypotension. 8 AGONIST TAPER METHADONE 9 Tapering off opioids with methadone appears to reduce the severity of withdrawal symptoms, but the majority of patients still relapse to opioid use if a strategy involving only withdrawal management is employed. 10 Methadone at tapered doses does not appear to differ from other pharmacological treatments (e.g., adrenergic agonists, other opioid agonists) in terms of treatment completion, sustained abstinence, severity of withdrawal symptoms, or adverse effects. Compared to placebo, tapered methadone appears to be associated with less severe withdrawal symptoms and lower rates of drop-out. 9 It is important to note that wide variations in the literature were a major limitation when comparing tapered methadone to other treatments (e.g., different studies assessed different outcomes of withdrawal management using methadone versus other treatments, which did not allow for exact comparisons between treatment approaches in certain contexts). 9 AGONIST TAPER BUPRENORPHINE/NALOXONE 11 Similar to tapering off opioids with methadone, agonist taper involving buprenorphine/naloxone appears to reduce the severity of withdrawal symptoms, but the majority of patients still relapse to opioid use if a strategy involving only withdrawal management is employed. For instance, patients in the Prescription Opioid Addiction Treatment Study demonstrated significantly lower sustained abstinence rates eight weeks after tapering off buprenorphine/naloxone (8.6%) compared to success rates during buprenorphine/naloxone treatment (49.2%). 12 At least in inpatient settings, buprenorphine appears to be more advantageous compared to methadone, in terms of offering faster symptom relief and higher rates of treatment completion. There does not appear to be a significant difference in terms of withdrawal symptom severity for individuals managed with buprenorphine compared to methadone. 11 * Sometimes referred to as detoxification or detox 6

Buprenorphine is also more effective than alpha-2 adrenergic agonists (e.g., clonidine), as it appears to offer more effective relief of withdrawal symptoms and to promote longer retention in treatment and greater likelihood of completing treatment. 11 There does not appear to be a significant difference between buprenorphine and alpha-2 adrenergic agonists in terms of the incidence of adverse effects, except in the case of clonidine, which may be associated with greater drop-out due to adverse effects. 11 OTHER CONSIDERATIONS FOR TREATMENT USING WITHDRAWAL MANAGEMENT ONLY The lack of effectiveness of treatment using withdrawal management alone (e.g., without transition to long-term treatment) often rapidly leads to high rates of relapse post-treatment, which, in turn, increases the risk of HIV transmission, morbidity and mortality. 13,14 As the first point of engagement in clinical care, opioid withdrawal management can serve an important role as a bridge to further treatment, but is not recommended unless a strategy is in place for referral to ongoing intensive outpatient or residential treatment. Specifically, a meta-analysis found higher HIV incidence among individuals undergoing withdrawal management only compared with individuals receiving no treatment. 13 Other past research has shown that individuals who have received inpatient opioid withdrawal management are at increased risk of death from drug overdose compared to those who received no treatment. 14 This phenomenon is believed to be due to loss of tolerance to opioids and is consistent with the increased risk of fatal opioid overdose observed following release from prison. 15 Furthermore, relapse is common among patients undergoing withdrawal management only, with a significantly lower rate of abstinence at discharge (12%) compared to abstinence rates associated with other opioid treatment approaches (18 to 21%). 10,16 In order to reduce the risk of fatal overdose among high-risk patients, take-home naloxone prescriptions ought to be considered as a safe and effective fatal overdose prevention strategy. 17,18 PSYCHOSOCIAL SUPPORTS PROVIDED WITH WITHDRAWAL MANAGEMENT Psychosocial supports appear to be beneficial adjuncts to opioid withdrawal management. 19 When offered in addition to pharmacologically-supported withdrawal management (i.e., taper with opioid medication), psychosocial therapies such as contingency management and psychotherapeutic counselling are effective in terms of improving treatment retention and completion, sustaining abstinence from illicit opioids, and reducing opioid use during treatment. However, there is currently limited evidence due to small study sample sizes and varying assessment and outcome measurements. There is also insufficient evidence to favour any specific psychosocial approach. 19 Therefore, further research and patient-specific approaches are needed with regard to psychosocial treatments. Importantly, while psychosocial treatments may improve rates of treatment retention and completion, psychosocial treatments provided during opioid withdrawal management likely do not protect against the elevated risk of HIV infection or fatal overdose if withdrawal management alone is pursued, due to high rates of relapse post-treatment and the negligible benefit of withdrawal management alone. 12 14,20 RESIDENTIAL TREATMENT There are no systematic reviews or meta-analyses considering the impacts of residential treatment programs for individuals with opioid use disorder. The overall dearth of evidence does not mean 7

residential treatment is ineffective, but rather that the intervention has been under-studied, thus requiring review of individual studies. There are also no large clinical trials comparing residential treatment to other interventions and there are few rigorous evaluations that would help identify specific characteristics of effective residential treatment programs or patient characteristics that may predict appropriateness of residential treatment referral. Among the evaluations that have specifically examined the impacts of residential treatment for opioid dependence, relapse has been shown to be relatively common among clients referred to residential treatment for opioid use disorder. Smyth et al. (2010) evaluated patients with opioid use disorder admitted to a six-week residential treatment program with methadone withdrawal management, psychosocial therapies (e.g., group, individual and/or family therapy) and an aftercare component. The study found that 80% reported relapse within one month, of whom 59% relapsed within one week of discharge. 21 Additionally, younger age, failure to complete six weeks of treatment, greater heroin use prior to treatment, history of injecting and a failure to enter aftercare were associated with a shorter time to relapse. In a study conducted among clients recruited from over 20 residential treatment programs (using methadone, lofexidine or codeine for withdrawal management, with the goal of achieving abstinence from opioids) in the United Kingdom, 22 clients demonstrated improvements in terms of reduced injecting, sharing of injection equipment, heavy drinking and criminal behaviour after residential treatment. 23 A follow-up study of this cohort found that approximately 57% of clients used heroin within 30 days of discharge from residential treatment. 24 Longer stays in treatment were predictive of better one-year outcomes. Studies of residential treatment in the United States also present varied results. When data up to 42 months after trial enrolment were considered in the Prescription Opioid Addiction Treatment Study, it is noteworthy that the greatest predictor of abstinence was being on agonist therapy, but also that more than 30% of patients diagnosed with opioid addiction were abstinent from opioids and not on agonist therapy. 25 One longitudinal study found similar rates of treatment retention, completion and patient satisfaction among individuals in outpatient and residential treatment programs. 26 Similarly, one randomized trial found that patients enrolled in residential treatment for less than seven weeks showed no significantly different outcomes compared to patients who did not receive any type of treatment. 27 For patients enrolled in residential treatment for more than seven weeks, improved outcomes were observed, including increased likelihood of employment or enrolment in school, decreased likelihood of criminal conviction or incarceration, and decreased likelihood of heroin use, compared to patients who did not receive any type of treatment. 27 An additional study found that a four-week residential treatment program significantly decreased several maladaptive cognitive and behavioural patterns that may contribute to ongoing substance use problems in opioid-dependent adults. 28 Another randomized clinical trial found that a combination of community reinforcement and family training in addition to residential withdrawal management using buprenorphine, particularly when involving the adult patient s parents, was positively and significantly associated with improved retention in treatment and reductions in opioid and other drug use. 29 Therefore, patients may benefit from residential treatment that involves fostering family and other social connections. 8

Importantly, concerns regarding fatal overdose as a result of loss of tolerance during residential treatment without agonist therapy should be considered. In this regard, there is evidence from a national UK-based study that residential treatment is associated with reduced rates of overdose. 30 Nevertheless, health care providers must be vigilant in assessing for risk of relapse and consider implementing strategies to reduce the risk of fatal overdose (e.g., take-home naloxone, sterile syringe provision, starting opioid agonist therapy), given the known protective effects of these strategies against opioid use and related harms, particularly when individuals leave or are discharged from residential treatment and are at high risk of relapse. 31 II Agonist maintenance treatments Overall, as described below, opioid agonist maintenance treatments have been shown to be superior to withdrawal management in terms of retention in treatment, sustained abstinence from opioid use, and reduced risk of morbidity (e.g., HIV transmission) and mortality. The choice of agonist treatment depends on several patient-specific factors such as initial presentation, comorbidities (e.g., liver disease, prolonged QT), treatment preference, and response to treatment, as discussed below. Regardless of type of treatment administered, agonist maintenance treatment should incorporate long-term addiction monitoring, including regular followup, urine drug screens and mental health care. METHADONE Methadone has been shown to be significantly more effective than non-pharmacological outpatient treatment approaches in terms of treatment retention and suppression of heroin use. 32 Methadone at higher doses (e.g., between 60 120 mg/day or higher) is more effective than lower doses in terms of treatment retention and reducing heroin and cocaine use during treatment. 33,34 Methadone maintenance treatment has also been shown to reduce injection risk behaviours and the overall risk of hepatitis C and HIV infection among people who inject drugs. 13,35,36 Furthermore, among HIVpositive individuals, engagement in methadone maintenance therapy is independently associated with increased adherence to antiretroviral therapy and improved virologic outcomes (e.g., lower HIV viral loads, higher CD4 counts), particularly at higher doses ( 100 mg/day). 37 39 While methadone dosing should be based on clinical judgment determined individually due to differences in individual metabolism, comorbidities (e.g., liver disease, prolonged QT) and drug interactions, 40 most studies have suggested that patients who take daily doses of 80 mg/day or higher have optimal treatment outcomes 33 and that doses well above 120 mg/day may be required to produce full opioid blockade and fully suppress withdrawal. 41,42 Challenges with withdrawal have been reported with the recent transition in PharmaCare 9

coverage from methadone to Methadose in BC, likely related to change intolerance. 43 Where possible, providing methadone to those struggling with Methadose may have advantages. For induction and dosing guidelines for methadone maintenance treatment, practitioners are advised to refer to the College of Physicians and Surgeons of BC s Methadone Maintenance Program: Clinical Practice Guideline. 5 BUPRENORPHINE/NALOXONE Buprenorphine is superior to placebo in terms of greater treatment retention at doses greater than 2 mg/day, and greater suppression of illicit opioid use at doses greater than 16 mg/day. 44 Compared to methadone, buprenorphine at low doses ( 6 mg/day) is less effective in terms of treatment retention compared to low doses of methadone ( 40 mg/day). At medium and high doses, buprenorphine does not markedly differ from methadone in terms of treatment retention. Buprenorphine and methadone are equally effective in terms of reducing of illicit opioid use. 44 For induction and dosing guidelines for buprenorphine/naloxone maintenance treatment, refer to Appendix 1. COMPARING METHADONE TO BUPRENORPHINE/NALOXONE Early trials comparing buprenorphine to methadone have been critiqued for often employing relatively low buprenorphine doses and buprenorphine induction approaches that are slower than the current practice standards. 45 Newer studies show that sublingual buprenorphine achieves essentially equivalent outcomes to methadone when a sufficient dose, appropriate induction rate and flexible dosing are used. 45 Regarding side effects and adverse events, buprenorphine as a partial opioid agonist may be preferable in terms of reduced overdose potential. 45 One recent study of more than 19 million prescriptions over a six-year period in the United Kingdom found that buprenorphine is six times safer than methadone in terms of overdose risk. 46 Additionally, recent provincial mortality data indicate that methadone is implicated in approximately 25% of prescription-opioid-related deaths in British Columbia. 47 Other studies have found that methadone has a four-fold higher risk of fatal overdose and a significantly higher risk of non-medical or other problematic use compared to buprenorphine. 48,49 It is also worth noting that recent reports and a recent expert panel have highlighted the substantial risks of fatal overdose during methadone treatment initiation. 50,51 Buprenorphine has lower potential for respiratory depression and is well below the threshold lethal dose for opioid-naïve adults compared to standard methadone doses for opioid use disorder that often exceed the threshold lethal dose. 49 Furthermore, methadone has higher potential for adverse drug drug interactions with many common medications (e.g., antibiotics, antidepressants, antiretrovirals), as well as increased risk of cardiac arrhythmias as a 10

result of QT prolongation. 52 Patient-reported concerns with methadone include the potential for tooth decay, which has been largely under-acknowledged by care providers. 53,54 Additionally, because of its partial agonist effect, it is easier to switch from buprenorphine/naloxone to methadone, supporting buprenorphine/naloxone as a preferred firstline option in the absence of contraindications. 55,56 However, buprenorphine/naloxone may not be feasible for all patients due to individual patient factors, including intolerable symptoms during the prerequisite partial opioid withdrawal that is required for initiation of buprenorphine/naloxone treatment, in contrast to methadone treatment. 57 Consistent with the relative safety profile of buprenorphine/ naloxone in comparison to methadone, it is noteworthy that Alberta, Ontario, Nova Scotia and Quebec do not require physicians to have a federal Section 56 exemption from the Controlled Drugs and Substances Act in order to prescribe buprenorphine/naloxone. In BC, PharmaCare coverage is undergoing changes to allow access to buprenorphine/ naloxone without requiring that patients first try methadone. Historically, coverage has been restricted to patients for 6x Buprenorphine has a six times greater safety profile than methadone in terms of overdose risk 25% Methadone is implicated in 1 in 4 prescriptionopioid-related deaths in BC whom methadone treatment was inadequate or contraindicated (e.g., high risk of QTc prolongation, intolerance or hypersensitivity to methadone). 58 Regarding outcomes related to polysubstance use, while opioid agonists are not specifically intended for the treatment of cocaine addiction, past meta-analyses have shown that effective treatment of opioid addiction reduces cocaine use in polysubstance-using individuals using both heroin and cocaine. 59 To this end, a recent Cochrane review has suggested that methadone and buprenorphine/naloxone are no different in suppressing cocaine use. 44 In terms of cost effectiveness, the Canadian Agency for Drugs and Technologies in Health has recently noted that, while no Canada-specific studies have been completed, there is evidence that there may be cost-effective benefits of buprenorphine/naloxone in comparison to methadone. 60 Here, the major potential for cost savings is primarily due to the reduced pharmacy dispensation fees enabled through more flexible take-home dosing schedules that are safe and feasible with buprenorphine/naloxone. 61 64 In terms of gender-related differences, while opioid use is generally more prevalent among males, 11 there do not appear to be significant gender-related differences in outcomes associated with buprenorphine/ naloxone compared to methadone treatment. 65,66 Further research is needed since few studies have examined gender-based outcomes; 11 however, forthcoming systematic reviews may provide insight on potential gender-related differences in outcomes related to opioid agonist therapy. 67 11

Table 2. Advantages and disadvantages of methadone vs. buprenorphine/naloxone METHADONE Potent opioid agonist Potentially better treatment retention, particularly for severely unstable opioid-dependent individuals (e.g., injectors) who may be more prone to drop-out No precipitated withdrawal/easier to initiate treatment Potentially better alternative if buprenorphine was unsuccessful in relieving withdrawal symptoms, or was associated with severe side effects Approved in Canada for the primary purpose of pain control (as split dose BID or TID dosing; Health Canada exemption to prescribe methadone for analgesia also required) METHADONE Higher risk of overdose, particularly during treatment initiation Generally requires daily witnessed ingestion More severe side effect profile (e.g., sedation, weight gain, erectile dysfunction) More expensive if daily witnessed ingestion required Longer time to achieve therapeutic dose (> 35 days) Higher potential for adverse drug-drug interactions (e.g., antibiotics, antidepressants, antiretrovirals) Higher risk of non-medical or other problematic use Increased risk of cardiac arrhythmias as a result of QTc prolongation References ADVANTAGES BUPRENORPHINE/NALOXONE Less risk of overdose due to partial agonist effect and ceiling effect for respiratory depression (in the absence of benzodiazepines or alcohol) Reduced risk of injection, diversion, and overdose due to naloxone component, allowing for safer take-home dosing schedules Milder side effect profile Easier to rotate from buprenorphine/naloxone to methadone More flexible take-home dosing schedules may contribute to increased cost savings and patient autonomy Shorter time to achieve therapeutic dose (1 3 days) Potentially more effective analgesic for treatment of concurrent pain (however, see disadvantages) Fewer drug interactions Milder withdrawal symptoms and easier to discontinue, thus may be a better option for individuals with lower intensity opioid dependence (e.g., oral opioid dependence, infrequent opioid users, infrequent or non-injectors, short history of opioid dependence) and individuals anticipated to be successfully tapered off maintenance treatment in a relatively short period of time DISADVANTAGES BUPRENORPHINE/NALOXONE Potentially higher risk of drop-out May cause precipitated withdrawal if induced inappropriately Doses may be suboptimal for individuals with high opioid tolerance May block opioid analgesics used for concurrent pain treatment Not approved in Canada for the primary purpose of pain control 1. Maremmani I, Gerra G. Buprenorphine-based regimens and methadone for the medical management of opioid dependence: selecting the appropriate drug for treatment. Am J Addict 2010;19:557-68. 2. Bonhomme J, Shim RS, Gooden R, Tyus D, Rust G. Opioid addiction and abuse in primary care practice: a comparison of methadone and buprenorphine as treatment options. J Natl Med Assoc 2012;104:342-50. 3. Centre for Addiction and Mental Health (CAMH). Opioid Dependence Treatment Core Course. Module 2: Treatment Options. Choosing between methadone and buprenorphine maintenance treatment. May 2015 12

III Alternative agents SLOW-RELEASE ORAL MORPHINE * Since November 2014, slow-release oral morphine (24-hour formulation) has been approved by Health Canada s Non-Insured Health Benefits (NIHB) Program for the treatment of opioid use disorder. 68 Limited preliminary evidence suggests that slow-release oral morphine prescribed for maintenance treatment may reduce illicit opioid use and depressive symptoms. 69 However, slow-release oral morphine did not appear to make a significant difference in treatment retention compared to methadone treatment, and the risk of adverse events may be greater with slow-release oral morphine. 69 Since this preliminary evidence was published, a number of more recent trials have suggested that slow-release oral morphine may be a beneficial alternative to methadone treatment. For instance, a recent clinical trial found that patients treated with slow-release oral morphine demonstrated shorter QTc intervals, decreased heroin cravings and reduced dysthymic symptoms when compared with patients treated with methadone. 70 Another study found that slow-release oral morphine was superior to methadone in terms of reduced cravings, patient preference and reduced side effects, with similar outcomes to methadone in terms of drug use and physical and psychological health. 71 A multi-centre study of patients intolerant to or insufficiently responding to methadone found that transitioning patients from methadone to slowrelease oral morphine was relatively easy and well tolerated, and significant advantages were observed after switching to slow-release oral morphine (e.g., reduced withdrawal symptoms, reduced cravings, physical and psychological improvements). 72 For induction and dosing guidelines for slow-release oral morphine, refer to Appendix 2. DIACETYLMORPHINE Among patients who are treatment refractory to methadone, prescription diacetylmorphine (original trade name Heroin) administered in a clinic setting may be beneficial in terms of reducing illicit substance use, criminal activity, incarceration, mortality and drop-out. 73 While still considered an experimental treatment in Canada, this treatment is an established standard of care in other settings and generally involves flexible doses of supplementary oral methadone at the patient s and clinician s discretion. However, because of concerns about possible diversion and higher rates of adverse events (e.g., concurrent use of other illicit drugs leading to risk of overdose or seizures, continued use of needles with attendant risks of venous disease), 73 prescription of diacetylmorphine is generally only provided within highly supervised clinic settings for patients who have repeatedly failed other treatment approaches. Evaluations of cost effectiveness have suggested that, for patients who responded poorly to methadone maintenance treatment, diacetylmorphine significantly reduced use of illicit heroin compared to methadone treatment, and realized significant cost savings primarily related to reduced criminal activity. 74,75 Diacetylmorphine also appears to be associated with slightly superior outcomes related to social functioning, in comparison with reinitiating methadone treatment in individuals previously unsuccessfully treated with methadone. 73 * Note: Slow-release oral morphine refers to the 24-hour formulation of extended-release morphine capsules. 13

Comparisons between diacetylmorphine and hydromorphone are currently limited. 76,77 Notably, a small number (n=50) of former patients from the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) are maintained on injectable and oral hydromorphone. Other injectable medications, such as intravenous methadone, have also not been extensively studied. 74 Further, no studies have yet compared injectable diacetylmorphine to treatment with buprenorphine/naloxone. Although diacetylmorphine has been available for treatment of opioid dependence for several years in other countries (e.g., United Kingdom, Switzerland and other European countries), 78 currently the treatment is only accessible in Canada through Health Canada s Special Access Programme. ANTAGONIST TREATMENTS Naltrexone is an opioid receptor antagonist that blocks the euphoric effects of opioids at adequate doses. 79 Potential benefits of naltrexone include its ease of administration, its lack of induced tolerance during long-term treatment, and its pharmacological makeup that is not addictive or prone to abuse. 80 However, as an opioid antagonist, naltrexone fully blocks the effects of all opiate medications, including opioid analgesics prescribed for pain. Additionally, the reduced tolerance to opioids facilitated by the use of naltrexone may increase the risk of overdose for patients who subsequently relapse to opioid use, as demonstrated by a non-randomized study of naltrexone-associated mortality rates that were three to seven times higher than methadone-related mortality rates in Australia. 81 Presently, oral naltrexone is not scientifically proven to be superior to other forms of treatment for opioid use disorder. 82 Limited evidence suggests that there are no significant differences in maintenance treatment using oral naltrexone compared to placebo (except reduced incarceration in two studies), psychotherapy (based on a single study), benzodiazepines (based on a single study), or buprenorphine (based on a single study). 82 Treatment retention rates appear to be low with oral naltrexone maintenance treatment (28%). 82 However, a recent randomized trial observed fewer positive urine tests among individuals on oral naltrexone compared to placebo. 83 In the United States, extended-release naltrexone is available via monthly intramuscular injection, 84 which may promote improved treatment adherence in comparison to oral naltrexone. 79 Injectable naltrexone has demonstrated efficacy compared to placebo in terms of improved retention in treatment, increased abstinence and decreased opioid cravings. 85 87 Presently, extended-release naltrexone is only available in Canada for research purposes or through Health Canada s Special Access Programme. However, it is noteworthy to mention that there appears to be a high level of willingness to take extended-release naltrexone among 52% of opioid users in two cohort studies of people who use illicit drugs in Vancouver. 88 IV Combination approaches and movement between approaches Due to high rates of polysubstance use (e.g., cocaine and heroin) among opioid-dependent individuals in Lower Mainland British Columbia, it is important to stress the value of combining opioid agonist or antagonist treatments with residential treatment, which may allow for psychosocial strategies to reduce cocaine use (e.g., counselling, contingency management) to be coupled with treatments proven to promote abstinence from heroin use. This may be particularly valuable given the evidence in support of changing the environment of individuals who are seeking treatment for concurrent opioid and 14

cocaine dependence, but are severely addicted and actively using. 89,90 Of note, methadone doses may need adjustment as patients transition into and out of cocaine abstinence, as cocaine is a CYP inducer that can increase metabolism of methadone. 91 Regarding transitions between agonist medications, several trials show feasibility when converting to buprenorphine from low to moderate methadone doses of up to 60 70 mg/day. 92 In general, this practice must be individually tailored, but ideally involves a reduction of the methadone dose to 30 mg per day or less, if possible, for a minimum of one week prior to inducing buprenorphine. Then, buprenorphine/ naloxone should be introduced according to induction guidelines (see Appendix 1) no sooner than 24 hours after the last dose of methadone. 93 When transitioning from methadone doses that are greater than 70 mg/day, there is an increased risk of significant opioid-withdrawal-related discomfort and consequent risk of relapse. To mitigate this, adjunct medications and/or inpatient treatment may be required for rotation to buprenorphine/naloxone from higher doses of methadone. 92 Conversely, rotation from buprenorphine to methadone is relatively uncomplicated, as methadone is a full agonist and buprenorphine is a partial agonist. Established protocols for rotating between agonist therapies are available, and some guidance is provided in the College of Physicians and Surgeons of British Columbia s Methadone Maintenance Program: Clinical Practice Guideline. 5 Given the relatively superior safety profile of buprenorphine/naloxone (in the absence of concurrent alcohol or benzodiazepine ingestion), 61 64 and similar overall costs of methadone versus buprenorphine/ naloxone treatment, 94 research has investigated the feasibility of a stepped care strategy involving initiating agonist treatment with buprenorphine/naloxone followed by methadone among buprenorphine/naloxone treatment non-responders in comparison to initiating agonist treatment with methadone. 95 This study found that the stepped treatment approach was equally efficacious compared to optimally delivered methadone maintenance treatment, and concluded that collective data on the comparatively advantageous safety profile of buprenorphine were sufficient to warrant broader implementation of buprenorphine as a first-line treatment for opioid use disorder. There is currently limited evidence to guide strategies for transitioning off agonist therapies among patients who have achieved long-term abstinence from opioid use. The majority of tapers from methadone maintenance treatment appear to be unsuccessful (approximately 87%), but there are increased odds of success when doses are reduced gradually with longer periods of stabilization. 96 Specifically, an evaluation of the British Columbia methadone program found a successful taper completion rate of only 13% across 4,917 treatment episodes, with 35% of patients re-entering treatment within 18 months and 24% subsequently hospitalized for opioid-related reasons. 96 Longer, more gradual stepped-tapering schedules (e.g., > 52 weeks) in which dosages decrease in no more than half of the weeks during the total taper period were significantly more likely to result in success. 96 Gradual tapering in a therapeutic manner at an appropriate time for the patient may be advantageous, as demonstrated by a review of voluntary therapeutic detoxification patients who demonstrated a 48% pooled abstinence rate compared to a pooled abstinence rate of 22% among non-voluntary, nontherapeutic detoxification patients. 97 Finally, while there is limited evidence to guide strategies involving multiple attempts using a specific type of opioid substitution treatment, practitioners should be aware that patients may often require 15